Hepatitis C (HCV) belongs to the Flaviviridae family of positive-sense, single-stranded RNA viruses. The HCV genome encodes a polyprotein of about 3000 amino acid residues, which is processed into both structural and nonstructural proteins. HCV infection is a significant global health issue; the World Health Organization estimates that over 170 million people carry the HCV infection, which can ultimately result in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has been reported that those complications are responsible for about 10,000-20,000 deaths annually in the U.S. alone, and that HCV is the leading cause of advanced liver disease and the leading underlying cause for liver transplantation. Current therapies for HCV infection rely on the combination of interferon-α (IFN) and ribavirin. This treatment regimen reportedly causes undesirable side effects such as leucopenia, thrombocytopenia, and hemolytic anemia, with the added disadvantage that only about 50% of patients achieve a sustained viral response. Recently, new protease inhibitor drugs, namely Vertex's telaprevir and Merck's boceprevir, were added to the ribavirin and IFN combination, which were each found to shorten the treatment time and significantly increase the percentage of patients achieving a sustained viral response. However, the problem of ribavirin and IFN toxicity is still a serious setback. (see, for example, Hanazaki, Curr. Med. Chem.: Anti-Infect. Agents 2003, 2, 103; Lauer & Walker, N. Engl. J. Med. 2001, 345, 41; Gordon &. Keller, J. Med. Chem. 2005, 48, 1; Tan et al., Nat. Rev. Drug Discovery 2002, 1, 867; Idno & Bellobuono, Curr. Pharm. Des. 2002, 8, 959; Di Bisceglie et al., Hepatology 2002, 35, 224; Samuel, Clin. Microbiol. Rev. 2001, 14, 778; Klibanov et al., 2011, Pharmacotherapy 31, 951; Kwo & Zhao 2011, Clink Liver Dis. 15, 537; the foregoing publications, and each additional publication cited herein, are incorporated herein by reference). Thus, more effective and less toxic anti-HCV therapeutics are greatly needed.
Another member of the Flaviviridae family of positive-sense, single-stranded RNA viruses is the Bovine Viral Diarrhea Virus (BVDV). Infection with this virus brings about a severe mucosal disease in cattle and other ruminants as well as pigs. BVDV cattle infections are marked by nose, mouth and gastrointestinal mucosa ulceration, which cause continuous salivation, nasal discharge, coughing and/or diarrhea. As a result there is a quick virus spread among animals. The virus also causes calves to be still born, become persistently infected, or suffer growth retardation and/or display severe neurological malformations. The economic impact of BVDV is considerable, although it is difficult to precisely estimate its level since certain infections remain undiagnosed or the losses are not recognized as being due to the virus. (see, for example, Buckwold et al., Antivirus Research 2003, 60, 1; Finkielsztein et al., 2010, Current Medicinal Chemistry 17, 2933). Other members of this Flaviviridae family of diseases include West Nile Virus and Dengue Fever. Thus effective therapeutics will be useful for reducing the economic impact of BDVD, West Nile Virus and Dengue Fever.
Acquired immune deficiency syndrome (AIDS) (1) is a disease brought about by a retrovirus termed human immunodeficiency virus (HIV), which belongs to Retroviridae and Lentivirus families. This condition causes a gradual decline of the immune system and leaves the HIV-infected individuals susceptible to opportunistic infections and to tumor formation that eventually leads to death. To alleviate these devastating ills the pharmaceutical community came up with an active antiretroviral therapy. It involves a cocktail of HIV protease and reverse transcriptase inhibitor drugs. This therapy brings about a significant improvement in the general health and quality of life of many HIV-infected individuals. This recovery is also associated with a marked reduction in HIV-associated morbidity and mortality. Yet, the HIV protease and reverse transcriptase inhibitor drug cocktail does not cure the patient of the HIV infection nor does it prevent the return of AIDS, once the treatment is stopped. Thus, patients who withdraw from the therapy do not benefit from the treatment. Moreover, for a considerable fraction of AIDS patients this treatment achieves far less than optimal results because the therapy intolerance, therapy side effects or infection with a drug-resistant HIV strain. To overcome these limitations, there is a need for additional effective anti-HIV drugs, and in particular, anti-HIV drugs that are less toxic. (see, for example, Sepkowitz 2001, N. Engl. J. Med. 344, 1764; Weiss 1993, Science 260, 1273; Dybul et al. 2002, Ann. Intern. Med. 137, 381; Martinez-Picado et al. 2000, Proc. Natl. Acad. Sci. U.S.A. 97, 10948.
Another family of RNA viruses are the coronaviruses, which are species of virus belonging to the subfamily Coronavirinae in the family Coronaviridae. Coronaviruses are enveloped viruses with a positive-sense RNA genome and with a nucleocapsid of helical symmetry. Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. Four to five different currently known strains of coronaviruses infect humans. One of the more well-known strains of human coronavirus is SARS-CoV, which causes severe acute respiratory syndrome (SARS). Coronaviruses are also reported to cause a significant percentage of all common colds in humans. Coronaviruses are also reported to cause pneumonia, either direct viral pneumonia or a secondary bacterial pneumonia. Recently, Middle East respiratory syndrome coronavirus (MERS-CoV), a SARS-like coronovairus, has been reported in humans. Coronaviruses also infect livestock, such as chickens. The infectious bronchitis virus (IBV) is a coronavirus that targets not only the respiratory tract but also the uro-genital tract in chickens. The virus can also spread to different organs throughout the chicken.
Coronaviruses reportedly cause a range of diseases in farm animals and domesticated pets, including porcine coronavirus (transmissible gastroenteritis coronavirus, TGE), bovine coronavirus, each of which result in diarrhea in young animals, feline coronavirus, such as feline enteric coronavirus, of minor clinical significance, and feline infectious peritonitis (FIP), a disease associated with high mortality, canine coronavirus (CCoV), mouse hepatitis virus (MHV), and others. Thus, compounds, compositions and therapies are needed to treat coronavirus.
It has been discovered herein that piperidine and piperazine carboxamides, including the compounds described herein, are active antiviral agents. In particular, it has been discovered herein that piperidine and piperazine carboxamides are active anti-HIV agents. It has also been discovered herein that piperidine and piperazine carboxamides are active anti-HCV agents. It has also been discovered herein that piperidine and piperazine carboxamides are active against Flaviviridae viruses and related diseases. It has also been discovered herein that piperidine and piperazine carboxamides are active anti-BVDV agents. It has also been discovered herein that piperidine and piperazine carboxamides are active anti-West Nile virus agents. It has also been discovered herein that piperidine and piperazine carboxamides are active anti-Dengue viral agents. It has also been discovered herein that piperidine and piperazine carboxamides are active anti-coronavirus agents.
In one illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of HIV infections, AIDS, and AIDS-related diseases. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of HIV infections, AIDS, and AIDS-related diseases. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating HIV infections, AIDS, and AIDS-related diseases, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having an HIV infection, AIDS, and AIDS-related diseases.
In another illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of BVDV infections. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of BVDV infections. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating BVDV infections, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having a BVDV infection.
In another illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of West Nile virus infections. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of West Nile virus infections. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating West Nile virus infections, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having a West Nile virus infection.
In another illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of Dengue fever. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of Dengue fever. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating Dengue fever, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having a Dengue fever.
In another illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of HCV. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of HCV. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating HCV, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having an HCV infection.
In another illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are useful for the treatment of coronavirus infection, such as SARS-CoV and MERS-CoV infection. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides that are useful for the treatment of coronavirus infection, such as SARS-CoV and MERS-CoV infection. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating coronavirus infection, such as SARS-CoV and MERS-CoV infection, where the methods include administering the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides. In another embodiment, described herein is the use of one or more of the substituted piperidine and piperazine carboxamides and/or the pharmaceutical compositions including the substituted piperidine and piperazine carboxamides in the manufacture of a medicament for treating a patient or host animal having a coronavirus infection, such as a SARS-CoV or MERS-CoV infection.
In one illustrative embodiment, described herein are substituted piperidine and piperazine carboxamides that are effective in the treatment of viral diseases including HCV, BVDV, coronavirus, and/or HIV. In another embodiment, described herein are pharmaceutical compositions comprising the substituted piperidine and piperazine carboxamides, and methods for the use of the substituted piperidine and piperazine carboxamides, including pharmaceutical compositions containing them, in the treatment of viral diseases including HCV, BVDV, coronavirus and/or HIV.
In another embodiment, described herein is a pharmaceutical composition for treating a viral infection, where the composition includes (a) a therapeutically effective amount of one or more compounds of the formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein:
W is a nitrogen or a carbon;
X is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl, each of which is optionally substituted; or acyl;
RA is hydrogen or optionally substituted alkyl;
R is H, alkyl, heteroalkyl, acyl, alkoxycarbonyl, or aminocarbonyl, each of which is optionally substituted; or R is a prodrug moiety; and
Ar1 is aryl or heteroaryl, each of which is optionally substituted; and                (b) one or more pharmaceutically acceptable carriers, excipients, or diluents, or combinations thereof.        
In another embodiment, described herein are methods for treating a viral infection in a patient, the methods comprising the step of administering to the patient a therapeutically effective amount of one or more of the compounds described herein, or a therapeutically effective amount of one or more of the compositions described herein, or one or more of the unit doses or unit dosage forms described herein.
In another embodiment, described herein are uses of one or more compounds or compositions described herein in the manufacture of a medicament for treating a viral infection, where the medicament includes (a) a therapeutically effective amount of one or more of the compounds or compositions described herein; and optionally, (b) one or more carriers, excipients, or diluents, or combinations thereof.
In another embodiment, described herein are compositions, methods, and uses where the viral infection is a DNA or RNA viral infection. In another embodiment, described herein are compositions, methods, and uses where the viral infection is a hepatitis C viral infection. In another embodiment, described herein are compositions, methods, and uses where the viral infection is a HIV infection. In another embodiment, described herein are compositions, methods, and uses where the viral infection is a BVDV infection. In another embodiment, described herein are compositions, methods, and uses where the viral infection is a coronavirus infection.